The metabolic syndrome and type 2 diabetes have emerged as public health issues of considerable[unreadable] importance due to the magnitude of the problem and the associated high risk of atherosclerotic[unreadable] cardiovascular disease. New evidence supports a growing issue of increases in cardiovascular disease risk[unreadable] in people with Type 1 diabetes in part due to direct effects of glucose and evolving obesity in this population.[unreadable] The overall unifying theme is that components of the metabolic syndrome and diabetes leads to accelerated[unreadable] rates of atherosclerosis due to activation of key immune and inflammatory signals in the vascular wall and[unreadable] adipocytes. These factors further induce migration and activation of key cellular components into adipose[unreadable] tissue and the vascular wall. Aim#1--The hypothesis to be tested is that genetic or diet induced insulin[unreadable] resistance and diabetes will lead to accelerated inflammation, atherosclerosis, and macrophage infiltration[unreadable] into fat tissue. We will first characterize atherosclerosis progression in new mouse and porcine models of[unreadable] diabetes and the metabolic syndrome. The other key parameters that will be studied include analysis of[unreadable] visceral fat distribution (using DEXA) circulating adipokine production and evaluation of trafficking of[unreadable] macrophages into the visceral fat bed in collaboration with project 4. Aim#2--The goal of this aim is to[unreadable] specifically evaluate the role of 12/15 lipoxygenase (12/15-LO) and inflammatory pathways in visceral[unreadable] adipocytes and macrophages in vascular disease associated with the metabolic syndrome and diabetes.[unreadable] The hypothesis is that 12/15-LO activation participates in downstream inflammation in the vascular wall and[unreadable] visceral adipose tissue in large part by inducing activation and trafficking of macrophages. Aim#3?This is[unreadable] designed to test the hypothesis that key components of the innate immune system including toll like receptor[unreadable] 4 (TLR4) and the IL-12 family of cytokines participate in atherosclerosis in the insulin resistant and diabetic[unreadable] models. This overall project will utilize all cores and involve collaborations with Drs. Natarajan, McNamara,[unreadable] Ley, Hedrick, Gerrity, Susanna Keller, and Norbert Leitinger. The competitive renewal of our Project will[unreadable] utilize the latest cellular and molecular approaches and animal models to explore the mechanisms and new[unreadable] translational opportunities to reduce or prevent atherosclerotic cardiovascular disease associated with[unreadable] diabetes and the metabolic syndrome.